Aging of the human immune system is characterized by a gradual loss of immune function and a skewing of the hematopoietic cells toward the myeloid lineage, a reduction in the lymphocytic lineage, and progressive increases in senescent memory T cells at the expense of naove T cells. Both the innate and the adaptive branches of the immune system are affected, including neutrophils (PMN), macrophages, dendritic cells (DC) and lymphocytes. Even the hematopoietic stem cell (HSC) population is detrimentally affected by aging as reflected by its inability to maintain both hematopoiesis and lymphopoiesis. Mice, the most common research model, although inexpensive, do not necessarily reflect the human immune system in terms of its interaction with infectious agents of human origin or environmental factors. Therefore, a major challenge for immunologic gerontology is to develop a model that functionally mimics human immune senescence, is relatively inexpensive, and can be manipulated to explore the intricacies of aging. The model proposed for this study would be the first to express a complete and functional human immune system contained within an animal model that can be realistically used to evaluate the development and therapy of aging-related diseases. Successful completion of the proposed work should allow for the rapid and systemic evaluation of multiple environmental and genetic triggers, testing of clinical therapies for a variety of age-related diseases, as well as an assessment of the role of intrinsic and extrinsic factors on immune aging. Therefore, the project has the potential of widespread impact on the field of science and could potentially affect a large patient population. PUBLIC HEALTH RELEVANCE: We propose to transplant human cord blood (CB CD34+) stem cells into NOD-Rag1-/-3c-/- (NRG) mice to create a CB-NRG mouse. This model will allow us to manipulate critical variables correlated with the development and clinical treatment efficacy of human aging-related disease, while maintaining relevance to the human situation. The proposed study, if successful, should have a major impact that would be very broad as it would apply to current 20% of population that is considered aged, a population which continues to grow annually. Immune senescence has been well documented to be a contributor to frailty and mortality risk in the elderly. The proposed model would allow for experimental manipulations to improve understanding of the aging human immune system, as well as for investigation of novel interventions to improve function of the aging immune system. Such an understanding should have significant benefits in terms of dealing with infectious disease and improving methods for vaccination in the elderly.